3/11/2025 Ben Libman
Researchers in professor Shannon Sirk’s bioengineering lab are developing a system to harness gut bacteria for therapeutic protein delivery, with promising implications for treating inflammatory bowel disease and other gastrointestinal conditions. Their recent Nature Communications paper details how engineered Bacteroides species can secrete beneficial proteins directly into the gut or via protective outer membrane vesicles. This innovation, combined with precise control over protein production, could enable real-time, patient-specific treatments that respond to disease flare-ups. This research represents a crucial step in microbiome-based medicine.
Written by Ben Libman
Our microbiome is critical to our overall health. Scientists have only recently begun to understand the depths to which our overall wellbeing can be affected by the microorganisms in our gut. Beyond direct effects like digestion and metabolism, our microbiome can affect our immune system, energy levels, and even mental health. But can our microbiome do even more? Could it even treat disease?
This was the question bioengineering graduate students Yu-Hsuan Yeh, Vince Kelly, postdoc Rahman Rahman Pour, and bioengineering professor Shannon Sirk set out to answer. Their paper, recently published in Nature Communications, outlines a potential solution involving Bacteroides species. Bacteroides are some of the most abundant species in our gut, surviving there for years. If these Bacteroides were engineered to produce beneficial proteins, they could have tremendous positive effects on our overall health. However, there are significant obstacles to accomplishing this. Because Bacteroides are not as well studied as other organisms in our microbiome, we did not have a good understanding of how they secrete proteins. There was also a comparative lack of available tools for genetically engineering Bacteroides.
Professor Sirk’s lab has developed a system to get Bacteroides to make proteins they don’t normally produce and efficiently guide those proteins into the gut. They do this by fusing the proteins to specialized signal peptides the Bacteroides emit naturally, which guides them out of the cell. There are several pathways through which the protein leaves the cell. One is direct secretion, in which the protein leaves the Bacteroides and goes directly into the gut. The other pathways involve the outer membrane vesicles (OMVs), which are microscopic particles made of biological material that are released by some bacteria. Proteins made by the Bacteroides can be anchored to one of these OMVs or even encased fully inside them. The proteins inside may be protected from degradation while the proteins outside could help deliver the whole OMV package to a specific disease target.
Protein delivery is one half of the system. The other half is controlling how much protein the Bacteroides produce and when. This is done using an inducer molecule that binds to factors in the bacteria that turn on protein production. If there is no inducer in the system, the bacteria won’t produce the designated protein. When the researchers want them to start, they simply add the inducer. The Bacteroides are also responsive to the levels of inducer- they will create more or less of the protein depending on how much is present. This enables Sirk’s team to fine-tune the levels of protein secretion based on their needs.
This system holds immense medical potential, particularly for those with chronic gastrointestinal diseases such as inflammatory bowel disease (IBD). Right now, patients suffering from IBD have to go through an arduous process to get treatment that includes either invasive procedures or analysis of their feces, which usually takes days to weeks. Sirk’s lab is currently working on a biomarker sensing system for the Bacteroides, which has the potential to stop IBD symptoms before they start. The engineered gut bacteria could sense inflammatory flares as they begin and respond by producing the designated therapeutic protein, stopping inflammation in its tracks. These living diagnostics could also be deployed in cancer survivors in an effort to reduce tumor recurrence in the gut. In addition, this method could be used to help researchers study the human microbiome by enabling Bacteroides species to secrete signaling molecules for easier tracking.
There is still more work to be done. Though professor Sirk and her team engineered Bacteroides strains that survived in mice without negative side effects, human trials are still needed. But this therapy has the potential to revolutionize how we treat numerous diseases. The microbiome is a hugely important piece of our overall health. By working with it, Illinois researchers may improve the lives of millions. It’s another example of the Department of Bioengineering at The Grainger College of Engineering, University of Illinois Urbana-Champaign shaping the future of bioengineering.
The full paper is available here.
Shannon Sirk is an Assistant Professor in the Department of Bioengineering at The Grainger College of Engineering, University of Illinois Urbana-Champaign. Sirk is an affiliate of the Carle Illinois College of Medicine and the Institute for Genomic Biology.